Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds

ABSTRACT

The present invention provides new processes for the preparation of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds which are usefuil, for example, for preventing or treating diseases or conditions related to an abnormally high level or activity of TNF-α. The invention can provide improved and/or efficient processes for the commercial production of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds, including, but not limited to, unsubstituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/696,224, filed Jun. 30, 2005, which is incorporated herein byreference in its entirety.

2. FIELD OF THE INVENTION

The present invention provides processes for the preparation ofcompounds useful for reducing levels or activity of tumor necrosisfactor α in mammals. More specifically, the invention provides processesfor the preparation of unsubstituted and substituted4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione compounds.

3. BACKGROUND OF THE INVENTION

Excessive or unregulated production of tumor necrosis factor α or TNF-α,has been implicated in a number of disease conditions. These includeendotoxemia and/or toxic shock syndrome (Tracey et al., Nature 330,662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)),cachexia (Dezube et al., Lancet 335 (8690), 662 (1990)), and AdultRespiratory Distress Syndrome (Millar et al., Lancet 2 (8665), 712-714(1989)). Certain substituted2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines have been shown to reducelevels of TNF-α in the literature such as International Publication No.WO 98/03502 and Muller et al., Bioorg. Med Chem. Lett. 9, 1625-1630(1999).

A substituted isoindole-1,3-dione that has demonstrated certaintherapeutic values is 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(THALOMID™). This compound has been shown to be or is believed to beuseful in treating or preventing a wide range of diseases and conditionsincluding, but not limited to, inflammatory diseases, autoimmunediseases, cancers, heart diseases, genetic diseases, allergic diseases,osteoporosis and lupus.

Existing methods for synthesizing unsubstituted and substituted4-amino-2-(2,6-dioxopiperidin-3-yl) isoindole- 1,3-dione compounds aredescribed in U.S. Pat. Nos. 6,395,754 and 5,635,517. While these methodsare enabling and useful for preparing unsubstituted and substituted4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds,alternative or improved methods for their preparation, particularly inmanufacturing scale, are still needed.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

4. SUMMARY OF THE INVENTION

The present invention provides efficient processes for the preparationof unsubstituted and substituted4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds,particularly the unsubstituted4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

In one aspect, the invention provides a process for preparing anunsubstituted or substituted4-amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione compound ofFormula (I):

or a pharmaceutically acceptable salt, solvate including a hydrate, orpolymorph thereof, wherein the process comprises the step of cyclizingan N-(3-aminophthaloyl)-glutamine compound of Formula (II) or anN-(3-aminophthaloyl)-isoglutamine compound of (IIA):

or a salt thereof with a cyclizing agent of Formula (V):

wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; and each of X and Y is independently an unsubstituted orsubstituted imidazolyl, benzimidazolyl or benzotriazolyl. In someembodiments, R¹ of Formula (I) or (II) is H.

In some embodiments, the cyclizing agent is a carbonyldiimidazolecompound of Formula (VI):

where each of R², R³, R⁴, R⁵, R⁶ and R⁷ is independently H, alkyl, halo,nitro, cyano, acyl, alkoxy, aryloxy, alkoxycarbonyl or alkoxymethyl. Ina particular embodiment, the carbonyldiimidazole compound is1,1′-carbonyldiimidazole (i.e., where each of R², R³, R⁴, R⁵, R⁶ and R⁷of Formula (VI) is H). In a further embodiment, the ratio of thecompound of Formula (II) to 1,1′-carbonyldiimidazole is from about 1:1to about 1:1.2.

In another embodiment, the cyclization occurs in acetonitrile. Inanother embodiment, the cyclization occurs in tetrahydrofuran. In afurther embodiment, the cyclization reaction temperature is from about80° C. to about 87° C. In another embodiment, the cyclization reactiontime is from about 1 hour to about 5 hours.

In another aspect, the invention provides a process for preparing anunsubstituted or substituted4-amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione compound ofFormula (I) or a pharmaceutically acceptable salt or solvate orpolymorph thereof, wherein the process comprises the step of reacting3-aminophthalic acid or a salt thereof with a 3-aminoglutarimidecompound of Formula (X) or a salt thereof:

in a solvent, wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,or (C₂-C₈)alkynyl. In some embodiments, R¹ of Formula (I) or (X) is H.

In certain embodiments, the reacting step occurs in the presence of abase, an acid or a combination thereof. In another embodiment, thereacting step occurs in the presence of a base which, in some instances,can be a trialkylamine, a substituted or unsubstituted imidazole or amixture thereof. In certain embodiments, the reacting step occurs in thepresence of the base and the acid where the base may be an amine such astriethylamine and the acid may be a carboxylic acid such as acetic acid.In certain embodiments, the mole ratio of triethylamine to acetic acidis from about 1:10 to about 1:1.

In another embodiment, the solvent is acetonitrile. In a furtherembodiment, the reaction temperature is about 85-87° C. In a furtherembodiment, the reaction time is from about 5 to about 7 hours.

5. DETAILED DESCRIPTION OF THE INVENTION

5.1 Terminology

As used herein and unless otherwise indicated, the term “halo”,“halogen” or the like means —F, —Cl, —Br or —I.

As used herein and unless otherwise indicated, the term “alkyl” or“alkyl group” means a saturated, monovalent, unbranched or branchedhydrocarbon chain. Examples of alkyl groups include, but are not limitedto, (C₁-C₈)alkyl groups, such as methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, heptyl, andoctyl. An alkyl group can be unsubstituted or substituted with one ortwo suitable substituents.

As used herein and unless otherwise indicated, the term “alkenyl” or“alkenyl group” means a monovalent, unbranched or branched hydrocarbonchain having one or more double bonds therein. The double bond of analkenyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkenyl groups include, but are not limited to(C₂-C₈)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

As used herein and unless otherwise indicated, the term “alkynyl” or“alkynyl group” means a monovalent, unbranched or branched hydrocarbonchain having one or more triple bonds therein. The triple bond of analkynyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkynyl groups include, but are not limited to, (C₂-C₈)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substitutedwith one or two suitable substituents.

As used herein and unless otherwise indicated, the term “substituted” asused to describe a compound or chemical moiety means that at least onehydrogen atom of that compound or chemical moiety is replaced with asecond chemical moiety. The second chemical moiety can be any suitablesubstituent that does not nullify the synthetic or pharmaceuticalutility of the compounds of the invention or the intermediates usefulfor preparing them. Examples of suitable substituents include, but arenot limited to: (C₁-C₈) alkyl; (C₂-C₈)alkenyl; (C₂-C₈)alkynyl; aryl;(C₂-C₅)heteroaryl; (C₁-C₆)heterocycloalkyl; (C₃-C₇)cycloalkyl;O—(C₁-C₈)alkyl; O—(C₂-C₈)alkenyl; O—(C₂-C₈)alkynyl; O-aryl; CN; OH; oxo;halo, C(O)OH; COhalo; O(CO)halo; CF₃, N₃; NO₂, NH₂; NH((C₁-C₈)alkyl);N((C₁-C₈) alkyl)₂; NH(aryl); N(aryl)₂; (CO)NH₂; (CO)NH((C₁-C₈)alkyl);(CO)N((C₁-C₈)alkyl)₂; (CO)NH(aryl); (CO)N(aryl)₂; O(CO)NH₂; NHOH;NOH((C₁-C₈)alkyl); NOH(aryl);O(CO)NH((C₁-C₈)alkyl);O(CO)N((C₁-C₈)alkyl)₂; O(CO)NH(aryl); O(CO)N(aryl)₂; CHO;CO((C₁-C₈)alkyl); CO(aryl); C(O)O((C₁-C₈)alkyl); C(O)O(aryl); O(CO)((C₁-C₈)alkyl)-; O(CO)(aryl); O(CO)O((C₁-C₈)alkyl); O(CO)O(aryl);S—(C₁-C₈) alkyl; S—(C₁-C₈)alkenyl; S—(C₁-C₈)alkynyl; and S-aryl. One ofskill in art can readily choose a suitable substituent based on thestability and pharmacological and synthetic activity of the compound ofthe invention.

As used herein and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20% by weight, more preferably less than about 10% byweight, even more preferably less than about 5% by weight, and mostpreferably less than about 3% by weight of the compound.

As used herein and unless otherwise indicated, the term“stereochemically pure” means a composition that comprises onestereoisomer of a compound and is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecomposition of a compound having one chiral center will be substantiallyfree of the opposite enantiomer of the compound. A stereomerically purecomposition of a compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center.

As used herein and unless otherwise indicated, the term “racemic” or“racemate” means about 50% of one enantiomer and about 50% of thecorresponding enantiomer relative to all chiral centers in the molecule.The invention encompasses all enantiomerically pure, enantiomericallyenriched, diastereomerically pure, diastereomerically enriched, andracemic mixtures of the compounds of the invention.

As used herein and unless otherwise indicated, the term “process(es) ofthe invention” or “process(es) of preparing” or “process(es) for thepreparation” refers to the methods disclosed herein which are useful forpreparing a compound of the invention. Modifications to the methodsdisclosed herein (e.g., starting materials, reagents, protecting groups,solvents, temperatures, reaction times, purification) are alsoencompassed by the present invention.

As used herein and unless otherwise indicated, the term “adding”,“reacting” or the like means contacting one reactant, reagent, solvent,catalyst, reactive group or the like with another reactant, reagent,solvent, catalyst, reactive group or the like. Reactants, reagents,solvents, catalysts, reactive group or the like can be addedindividually, simultaneously or separately and can be added in anyorder. They can be added in the presence or absence of heat and canoptionally be added under an inert atmosphere. “Reacting” can refer toin situ formation or intramolecular reaction where the reactive groupsare in the same molecule.

As used herein and unless otherwise indicated, a reaction that is“substantially complete” or is driven to “substantial completion” meansthat the reaction contains more than about 80% by percent yield, morepreferably more than about 90% by percent yield, even more preferablymore than about 95% by percent yield, and most preferably more thanabout 97% by percent yield of the desired product.

As used herein and unless otherwise indicated, the term“pharmaceutically acceptable salt” includes, but is not limited to,salts of acidic or basic groups that may be present in the compounds ofthe invention. Compounds of the invention that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. The acids that may be used to prepare pharmaceuticallyacceptable salts of such basic compounds are those that form saltscomprising pharmacologically acceptable anions including, but notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate,bitartrate, bromide, camsylate, carbonate, chloride, bromide, iodide,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,muscate, napsylate, nitrate, panthothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, succinate, sulfate, tannate,tartrate, teoclate, triethiodide, and pamoate. Compounds of theinvention that include an amino group also can form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Compounds of the invention that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Non-limiting examples of such salts include alkalimetal or alkaline earth metal salts and, particularly, calcium,magnesium, sodium, lithium, zinc, potassium, and iron salts.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound of the present invention or a salt thereof, that furtherincludes a stoichiometric or non-stoichiometeric amount of water boundby non-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound of the present invention. The term “solvate” includeshydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate, andthe like).

As used herein and unless otherwise indicated, the term “polymorph”means solid crystalline forms of a compound of the present invention orcomplex thereof. Different polymorphs of the same compound can exhibitdifferent physical, chemical and/or spectroscopic properties.

As used herein and unless otherwise indicated, the phrase “diseases orconditions related to an abnormally high level or activity of TNF-α”means diseases or conditions that would not arise, endure or causesymptoms if the level or activity of TNF-α were lower, or diseases orconditions that can be prevented or treated by a lowering of TNF-α levelor activity.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while apatient is suffering from the specified disease or disorder, whichreduces the severity or symptoms of the disease or disorder or retardsor slows the progression or symptoms of the disease or disorder.

Acronyms or symbols for groups or reagents have the followingdefinition: HPLC=high performance liquid chromatography,CH₃CN=acetonitrile; DMF=dimethyl formamide, DMSO=dimethyl sulfoxide,THF=tetrahydrofuran, CH₂Cl₂=methylene chloride andCDI=1,1′-carbonyldiimidazole.

If there is a discrepancy between a depicted structure and a name giventhat structure, the depicted structure is to be accorded more weight.Furthermore, if the stereochemistry of a structure or a portion thereofis not indicated, e.g., with bold or dashed lines, the structure orportion thereof is to be interpreted as encompassing all stereoisomersof it.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

5.2 Processes of the Invention

The present invention provides processes of preparing unsubstituted andsubstituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionecompounds. In general, the processes of the present invention mayencompass improved or efficient means for the large scale or commercialproduction of unsubstituted and substituted4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione compounds.

The unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds can be used to prepare pharmaceuticalcompositions and/or dosage forms for treating a wide range of diseasesand conditions including, but not limited to, inflammatory diseases,autoimmune diseases, cancers, heart diseases, genetic diseases, allergicdiseases, osteoporosis and lupus. In general, the pharmaceuticalcompositions can comprise at least one of the4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione compounds or apharmaceutically acceptable salt, solvate, polymorph or stereoisomerthereof. The pharmaceutical compositions can be administered to patientswho are treated for a wide range of diseases and conditions. Optionally,the pharmaceutical compositions can further comprise at least onecarrier, excipient, diluent, a second active agent or a combinationthereof. In some embodiments, the pharmaceutical compositions are usedin the preparation of individual, single unit dosage forms. Single unitdosage forms are suitable for oral, mucosal (e.g., sublingual, nasal,vaginal, cystic, rectal, preputial, ocular, buccal or aural), parenteral(e.g., subcutaneous, intravenous, bolus injection, intramuscular orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Non-limiting examples of dosage forms include tablets, caplets,capsules (e.g., soft elastic gelatin capsules), cachets, troches,lozenges, dispersions, suppositories, powders, aerosols (e.g., nasalsprays or inhalers), gels, liquid dosage forms suitable for oral ormucosal administration to a patient, including suspensions (e.g.,aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or awater-in-oil liquid emulsions), solutions and elixirs, liquid dosageforms suitable for parenteral administration to a patient, eye drops orother ophthalmic preparations suitable for topical administration, andsterile solids (e.g., crystalline or amorphous solids) that can bereconstituted to provide liquid dosage forms suitable for parenteraladministration to a patient.

In some embodiments, the invention provides processes for preparing4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds ofFormula (I):

or a pharmaceutically acceptable salt, solvate, polymorph orstereoisomer thereof, comprising the step of cyclizing anN-(3-aminophthaloyl)-glutamine compound of Formula (II), anN-(3-aminophthaloyl)-isoglutamine compound of (IIA) or a salt thereof:

with a cyclizing agent wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈) alkynyl.

In one embodiment, R¹ of Formula (I) and/or (II) is H. In a particularembodiment, R¹ of Formula (I) and/or (II) is (C₁-C₈)alkyl. In a furtherembodiment, R¹ of Formula (I) and/or (II) is methyl. In anotherembodiment, the solvate is a hydrate.

The cyclization of the compound of Formula (II) with the cyclizing agentcan occur in a solvent such as acetonitrile, ethyl acetate, acetone,methyl ethyl ketone, diethyl ether, tetrahydrofuran, dichloromethane,chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethylsulfoxide and combinations thereof. In one embodiment, the solvent isacetonitrile. In another embodiment, the solvent is boilingacetonitrile.

The reaction temperature can be any temperature useful for thecyclization reaction according to a person of ordinary skill in the art.For instance, in certain embodiments, the cyclization reactiontemperature can vary from about 20° C. to about 100° C. In someembodiments, the cyclization reaction temperature is from about 50° C.to about 90° C. In other embodiments, the cyclization reactiontemperature is from about 80° C. to about 87° C. In a particularembodiment, the cyclization reaction temperature is the boiling point(i.e., 81-82° C. at 1 atmospheric pressure) of acetonitrile.

The cyclization reaction time can be any time period useful for thecyclization reaction according to a person of ordinary skill in the art.For instance, in certain embodiments, the cyclization reaction time canvary from about 1 to about 24 hours, depending on the reactiontemperature. In general, the higher the reaction temperature, theshorter is the reaction time. In one embodiment, the solvent isacetonitrile, the reaction temperature is from about 80° C. to about 87°C., and the reaction time is from about 1 to about 5 hours.

The cyclizing agent can be any chemical that can cause a ring formationreaction between the amide group and the carboxylic group of Formula(II) or (IIA). In some embodiments, the cyclizing agent can have thefollowing formula:

where each of X and Y is independently an unsubstituted or substitutedimidazolyl, benzimidazolyl or benzotriazolyl. The cyclizing reagent ofFormula (V) can be purchased from a commercial supplier or preparedaccording to any method apparent to a person of ordinary skill in theart. For instance, the cyclizing agent of Formula (V) can be prepared byreacting phosgene (COCl₂) with an unsubstituted or substituted1H-imidazole compound, 1H-benzimidazole or 1H-benzotriazole. Thereaction between phosgene and a 1H-imidazole compound is described inBatey et al., Tetrahedron Lett., 1998, 39, 6267, which is incorporatedherein by reference. The reaction between phosgene and a1H-benzotriazole compound is described in Katritzky et al., J. Org.Chem., 1997, 62, 4155, which is incorporated herein by reference.

In some embodiments, the cyclizing agent is a carbonyldiimidazolecompound having the formula:

where each of R², R³, R⁴, R⁵, R⁶ and R⁷ is independently H, alkyl, halo,nitro, cyano, acyl, alkoxy, aryloxy, alkoxycarbonyl or alkoxymethyl.

The carbonyldiimidazole compound of Formula (VI) can be purchased from acommercial supplier or prepared according to any method apparent to aperson of ordinary skill in the art. For instance, thecarbonyldiimidazole compound of Formula (VI) can be prepared by reactingphosgene (COCl₂) with an unsubstituted or substituted 1H-imidazolecompound or a combination thereof. Some non-limiting examples of the1H-imidazole compound suitable for this invention include 1H-imidazole,2-methyl-1H-imidazole, 1H-imidazole-5-carbaldehyde,2-ethyl-1H-imidazole, 2-isopropyl-1H-imidazole,2-ethyl-5-methyl-1H-imidazole, 2-propyl-1H-imidazole,2-nitro-1H-imidazole, 5-nitro-1H-imidazole, methyl1H-imidazole-5-carboxylate, 4-(2-methoxyethyl)-1H-imidazole,2-methyl-5-nitro-1H-imidazole and 5-methyl-4-nitro-1H-imidazole, all ofwhich can be obtained from a commercial supplier such as AldrichChemicals, Milwaukee, Wis. or prepared by methods known to a person ofordinary skill in the art. Non-limiting examples of thecarbonyldiimidazole compound include 1,1′-carbonyldiimidazole,2,2′-dimethyl-1,1′-carbonyldiimidazole,2,2′-diethyl-1,1′-carbonyldiimidazole,2,2′-diisopropyl-1,1′-carbonyldiimidazole and2,2′-dinitro-1,1′-carbonyldiimidazole, all of which can be obtainedcommercially from a supplier such as Aldrich Chemicals, Milwaukee, Wis.or prepared by the method described above. In one embodiment, thecarbonyldiimidazole compound is 1,1′-carbonyldiimidazole.

In further embodiments, the cyclizing agent is selected from Formula(V), SOCl₂, POCl₃, derivatives of SOCl₂, derivatives of POCl₃, andcombinations thereof. The cyclization reaction can be further promotedor catalyzed by using a base in addition to the cyclizing agent. Thebase can be selected from the group consisiting of organic amines suchas triethylamine, pyridine, derivatives of pyridine and combinationsthereof.

In a particular embodiment, the 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound of Formula (I) can be prepared bycyclizing the N-(3-aminophthaloyl)-glutamine compound of Formula (II) ora salt thereof with 1,1′-carbonyldiimidazole (CDI) in refluxingacetonitrile for about 3 hours as depicted in Scheme A below.Alternatively, the same reaction can occur in N-methyl pyrrolidinone ortetrahydrofuran for a time period from about 13 to about 15 hours atroom temperature. In some embodiments, R¹ in Scheme A is H.

The ratio of the compound of Formula (II) to 1,1′-carbonyldiimidazolecan be any ratio useful for the cyclization reaction according to aperson of ordinary skill in the art. For instance, the ratio of thecompound of Formula (II) to 1,1′-carbonyldiimidazole can be from about2:1 to about 1:2. In some embodiments, the ratio of the compound ofFormula (II) to 1,1′-carbonyldiimidazole is from about 1:1 to about1:1.5. In other embodiments, the ratio of the compound of Formula (II)to 1,1′-carbonyldiimidazole is from about 1:1 to about 1:1.2. In oneembodiment, the cyclization of Formula (II) with1,1′-carbonyldiimidazole occurs in acetonitrile for 1 to 24 hours. Inanother embodiment, the cyclization of Formula (II) occurs in refluxingacetonitrile for 3 hours.

In another embodiment, the4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound ofFormula (I) can be prepared by cyclizing theN-(3-aminophthaloyl)-isoglutamine compound of Formula (IIA) or a saltthereof with 1,1′-carbonyldiimidazole (CDI) in a solvent, such asacetonitrile, N-methyl pyrrolidinone and tetrahydrofuran, as depicted inScheme A′ below. The reaction can occur at a temperature ranging fromabout room temperature to about 150° C. for about 30 minutes to about 24hours.

In one embodiment, the compound of Formula (I) can be a free amine.Optionally, the free amine of Formula (I) can be converted into an acidsalt by reacting the free amine of Formula (I) with the correspondingacid in a mole ratio of about 1:1. Some non-limiting examples ofsuitable acids include methanesulfonic acid, trifluoroacetic acid,4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, hydrochloricacid, nitric acid, sulfuric acid and phosphoric acid. In one embodiment,the 4-amino-2-(2,6-dioxo-3-piperidinyl) isoindole-1,3-dione of Formula(I) is converted into a hydrochloride salt with hydrochloric acid at atemperature from about 0° C. to about 22° C.

If a racemic compound of Formula (I) is desired, a racemicN-(3-aminophthaloyl)-glutamine compound of Formula (II) may be used inthe cyclization reaction. Conversely, if an enantiomerically purecompound of Formula (I) is desired, an enantiomerically pureN-(3-aminophthaloyl)-glutamine compound of Formula (II) may be used.Alternatively, if an enantiomerically pure compound of Formula (I) isdesired, a racemic mixture of Formula (I) may be prepared and thenresolved into the enantiomers by conventional resolution techniques suchas biological resolution and chemical resolution. In general, biologicalresolution uses a microbe which metabolizes one specific enantiomerleaving the other alone. In chemical resolution, the racemic mixture isconverted into two diastereoisomers that may be separated byconventional techniques such as fractional crystallization andchromatographies. Once separated, the diasteriosomeric forms may beconverted separately back to the enantiomers.

The compound of Formula (II) can be prepared by any method known to aperson of ordinary skill in the art. For example, the compound ofFormula (II) can be prepared by reducing the nitro group of the compoundof Formula (III) to an amine group as depicted in Scheme B below:

wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl. In some embodiments, R¹ in Scheme B is H.

Similarly, the compound of Formula (IIA) can be prepared by reducing thenitro group of the compound of Formula (IIIA) to an amine group asdepicted in Scheme B′ below:

In Schemes B and B′ above, the compounds of Formulae (III) and (IIIA)can be reduced to the compounds of Formulae (II) and (IIA) respectivelyby any reducing agent known in the art that can reduce a nitro group toa primary amine. Some non-limiting examples of such reducing agentinclude hydrogen plus a catalyst (catalytic hydrogenation), reducingmetals in an acid such as hydrochloric acid and acetic acid, sodiumsulfide in ammonium hydroxide solution, zinc in ammonium formatesolution, magnesium in hydrazinium monoformate solution and tindichloride in dilute hydrochloric acid. Some non-limiting examples ofsuitable hydrogenation catalyst include palladium metal (Pd), platinummetal (Pt), and derivatives and complexes of Pd and Pt. Thehydrogenation catalyst can be dissolved in a solvent; or dispersed orcoated on the surface of a catalyst support such as carbon and inorganicparticles such as alumina, silica, aluminum silicates and the like. Somenon-limiting examples of suitable reducing metals include iron, zincamalgam, zinc and tin. In a particular embodiment, the reducing agent ishydrogen plus a catalyst. In a further embodiment, the catalyst is a Pdcatalyst. In another embodiment, the catalyst is 5% Pd/C. In anotherembodiment, the catalyst is 10% Pd/C. Further, either wet or dryhydrogenation catalyst can be used.

The catalytic hydrogenation is generally carried out at a hydrogenpressure that drives the reaction to substantial completion. In aparticular embodiment, the catalytic hydrogenation is carried out at ahydrogen pressure from about 2.76 bars (i.e., 40 psi or 276 kPa) toabout 4.14 bars (i.e., 60 psi or 414 kPa).

In one embodiment, the catalytic hydrogenation is run at ambienttemperature. The catalytic hydrogenation is generally performed untilthe reaction is substantially complete. In a particular embodiment, thecatalytic hydrogenation is performed for about 1-24 hours at atemperature from about 15° C. to about 30° C. In a further embodiment,the catalytic hydrogenation is performed for about 2 to 3 hours at atemperature from about 18° C. to about 24° C.

In one embodiment, the catalytic hydrogenation occurs at a temperaturefrom about 18° C. to about 24° C. for about 2-3 hours in methanol in thepresence of 10% Pd/C. Either wet or dry hydrogenation catalyst can beused. In a further embodiment, the catalytic hydrogenation occurs at apressure from about 40 (2.76 bars or 276 kPa) to about 50 psi (3.45 barsor 345 kPa).

The catalytic hydrogenation can occur in a solvent. In one embodiment,the catalytic hydrogenation is conducted in a protic solvent, such asalcohols, water, and combinations thereof. In a further embodiment, thealcohol solvent is selected from the group consisting of methanol,ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol andcombinations thereof. In another embodiment, the catalytic hydrogenationis conducted in an apolar, aprotic solvent such as 1,4-dioxane. In yetanother embodiment, the catalytic hydrogenation is conducted in a polar,aprotic solvent such as acetone, DMSO, DMF and THF. In one embodiment,the solvent is a protic solvent. In a further embodiment, the solventfor catalytic hydrogenation is methanol. In further embodiments, solventmixtures are used.

If a racemic compound of Formula (II) or (IIA) is desired, a racemiccompound of Formula (III) or (IIIA) can be used. Conversely, if anenantiomerically pure compound of Formula (II) or (IIA) is desired, anenantiomerically pure compound of Formula (III) or (IIIA) can be used.Alternatively, if an enantiomerically pure compound of Formula (II) or(IIA) is desired, a racemic mixture of Formula (II) or (IIA) can beprepared and then resolved into the enantiomers by conventionalresolution techniques such as biological resolution and chemicalresolution.

The compound of Formula (III) can be prepared by any method known to aperson of ordinary skill in the art. For example, the compound ofFormula (III) can be prepared by reacting 3-nitrophthalic anhydride witha glutamine of Formula (IV) as depicted in Scheme C below. R¹ is asdefined above. In some embodiments, R¹ in Scheme C is H.

Similarly, the compound of Formula (IIIA) can be prepared by reacting3-nitrophthalic anhydride with an isoglutamine of Formula (IVA) asdepicted in Scheme C′ below. R¹ is as defined above. In someembodiments, R¹ in Scheme C′ is H.

The reaction between 3-nitrophthalic anhydride and the glutamine ofFormula (IV) or the isoglutamine of Formula (IVA) can occur in a solventsuch as acetonitrile, ethyl acetate, acetone, methyl ethyl ketone,diethyl ether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidinone, dimethyl formamide, dimethyl sulfoxide and combinationsthereof. In one embodiment, the solvent is dimethyl formamide.

The reaction temperature can be any temperature useful for the reactionof Scheme C or C′ according to a person of ordinary skill in the art.For instance, in certain embodiments, the temperature of the reactionbetween 3-nitrophthalic anhydride and Formula (IV) or (IVA) can be fromabout 20° C. to about 90° C. In some embodiments, the reactiontemperature is from about 40° C. to about 90° C. In other embodiments,the reaction temperature is from about 60° C. to about 90° C. In furtherembodiments, the reaction temperature is from about 80° C. to about 90°C.

The reaction time can be any time useful for the reaction of Scheme C orC′ according to a person of ordinary skill in the art. For instance, thereaction time can vary from about 1 hour to about 24 hours, depending onthe reaction temperature. In general, the higher the reactiontemperature, the shorter is the reaction time. In a particularembodiment, the reaction time is about 8 hours at a reaction temperaturefrom about 80° C. to about 90° C.

If a racemic compound of Formula (III) or (IIIA) is desired, a racemicglutamine of Formula (IV) or (IVA) can be used. Conversely, if anenantiomerically pure compound of Formula (III) or (IIIA) is desired, anenantiomerically pure glutamine of Formula (IV) or (IVA) can be used.Non-limiting examples of glutamine of Formula (IV) include D-glutamineand L-glutamine, both of which can be obtained from a commercialsupplier such as Aldrich, Milwaukee, Wis. Alternatively, if anenantiomerically pure compound of Formula (III) or (IIIA) is desired, aracemic mixture of Formula (III) or (IIIA) can be prepared and thenresolved into the enantiomers by conventional resolution techniques suchas biological resolution and chemical resolution.

The 3-nitrophthalic anhydride can be obtained commercially from asupplier such as Aldrich Chemical or prepared by any known method in theart. Further, the compound of Formula (VII) can be prepared by reactingmaleic anhydride with a glutamine of Formula (IV) according to theconditions described above for the reaction between 3-nitrophthalicanhydride with the glutamine compound of Formula (IV).

Alternatively, the compound of Formula (III) can be prepared accordingto the procedure depicted in Scheme D below. Referring to Scheme Dbelow, R¹ is as defined above and R⁸ is alkyl such as t-butyl or aralkylsuch as benzyl. In some embodiments, R¹ in Scheme D is H and R⁸ ist-butyl. In other embodiments, R¹ in Scheme D is H and R⁸ is benzyl.

Referring to Scheme D above, 3-nitrophthalimide can react with ethylchloroformate in a solvent in the presence of a catalyst such astriethylamine to form 3-nitro-N-ethoxycarbonyl-phthalimide. Somenon-limiting examples of suitable solvent include acetonitrile, ethylacetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran,dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide,dimethyl sulfoxide and combinations thereof. In one embodiment, thesolvent is dimethyl sulfoxide. The reaction temperature can be anytemperature useful for the reaction of according to a person of ordinaryskill in the art. For instance, in certain embodiments, the reactiontemperature can be from about 0° C. to about 5° C. The reaction time canbe any time useful for the reaction according to a person of ordinaryskill in the art. For instance, the reaction time can vary from about 1hour to about 24 hours, depending on the reaction temperature. Ingeneral, the higher the reaction temperature, the shorter is thereaction time. In a particular embodiment, the reaction time is about 4hours at 0-5° C.

The t-butyl or benzyl N-(3-nitrophthaloyl)-glutamine of Formula (IX) canbe purchased or prepared by reacting3-nitro-N-ethoxycarbonyl-phthalimide with a glutamine t-butyl or benzylester of Formula (VIII) or an acid salt thereof such as a hydrochloridesalt, where R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; and R⁸ is t-butyl or benzyl, in a solvent in thepresence of a catalyst such as triethylamine. In some embodiments, aracemic mixture of glutamine t-butyl ester hydrochloride is used toprepare of Formula (IX). In other embodiments, L-glutamine t-butyl esterhydrochloride is used to prepare of Formula (IX). In furtherembodiments, D-glutamine t-butyl ester hydrochloride is used to prepareof Formula (IX). Some non-limiting examples of suitable solvents includeacetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethylether, tetrahydrofuran, dichloromethane, chloroform, N-methylpyrrolidinone, dimethyl formamide, dimethyl sulfoxide and combinationsthereof. In one embodiment, the solvent is tetrahydrofuran. The reactiontemperature can be any temperature useful for the reaction of accordingto a person of ordinary skill in the art. For instance, in certainembodiments, the reaction temperature can be from about 25° C. to about100° C. The reaction time can be any time useful for the reactionaccording to a person of ordinary skill in the art. For instance, thereaction time can vary from about 1 hour to about 48 hours, depending onthe reaction temperature. In general, the higher the reactiontemperature, the shorter is the reaction time. In a particularembodiment, the reaction time is about 24 hours at about 65-66° C.

The reaction between hydrogen chloride and t-butylN-(3-nitrophthaloyl)-glutamine of Formula (IX) in a solvent can affordthe compound of Formula (III). Some non-limiting examples of suitablesolvent include acetonitrile, ethyl acetate, acetone, methyl ethylketone, diethyl ether, tetrahydrofuran, dichloromethane, chloroform,N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide andcombinations thereof. In one embodiment, the solvent is dichloromethane.The reaction temperature can be any temperature useful for the reactionof according to a person of ordinary skill in the art. For instance, incertain embodiments, the reaction temperature can be from about 0° C. toabout 100° C. The reaction time can be any time useful for the reactionaccording to a person of ordinary skill in the art. For instance, thereaction time can vary from about 1 hour to about 24 hours, depending onthe reaction temperature. In general, the higher the reactiontemperature, the shorter is the reaction time. In a particularembodiment, the reaction time is about 16 hours at about 20-25° C.

Referring to Scheme D, if a racemic compound of Formula (III) isdesired, a racemic t-butyl N-(3-nitrophthaloyl)-glutamine of Formula(VIII) can be used. Conversely, if an enantiomerically pure compound ofFormula (III) is desired, an enantiomerically pure t-butylN-(3-nitrophthaloyl)-glutamine of Formula (VIII) can be used.Alternatively, if an enantiomerically pure compound of Formula (III) isdesired, a racemic mixture of Formula (III) can be prepared and thenresolved into the enantiomers by conventional resolution techniques suchas biological resolution and chemical resolution. In general, biologicalresolution uses a microbe which metabolizes one specific enantiomerleaving the other alone. In chemical resolution, the racemic mixture isconverted into two diastereoisomers that can be separated byconventional techniques such as fractional crystallization andchromatographies. Once separated, the diasteriosomeric forms can beconverted separately back to the enantiomers.

In some embodiments, the compound of Formula (IIIA) can be preparedaccording to the procedures depicted in Scheme D′ below, which aresimilar to the procedures of Scheme D. Referring to Formulae (VIIIA),(IXA) and (IIIA), R¹ and R⁸ are as defined above. In some embodiments,R¹ in Scheme D′ is H and R⁸ is t-butyl. In other embodiments, R¹ inScheme D′ is H and R⁸ is benzyl.

Alternatively, the4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, polymorphor stereoisomer thereof, can be prepared by reacting 3-aminophthalicacid or a salt thereof with a 3-aminoglutarimide compound of Formula (X)or a salt thereof:

in a solvent, wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,or (C₂-C₈)alkynyl. In some embodiments, R¹ of Formula (X) is H.

The 3-aminoglutarimide compound can be purchased commercially from asupplier such as Evotec OAI, Hamburg, Germany; or prepared according tomethods described in the literature such as Capitosti et al., OrganicLetters, 2003, Vol. 5, No. 16, pp. 2865-2867, which is incorporatedherein by reference. In some embodiments, the 3-aminoglutarimidecompound of Formula (X) is 3-aminoglutarimide (i.e., where R¹ of Formula(X) is H) or its salt. Some non-limiting examples of suitable salts ofFormula (X) include carboxylic acid salts, methanesulfonic acid salt,trifluoroacetic acid salt, 4-(trifluoromethyl)benzoic acid salt,p-toluenesulfonic acid salt, hydrochloric acid salt, hydrobromic acidsalt, nitric acid salt, sulfuric acid salt and phosphoric acid salt.

The above condensation or coupling reaction between the 3-aminophthalicacid or a salt thereof and the compound of Formula (X) or a salt thereofmay occur in the presence of a catalyst. The catalyst may be a base, anacid such as a carboxylic acid, or a combination thereof. In someembodiments, the catalyst is or comprises a base. Some non-limitingexamples of suitable bases include alkali hydroxides, alkalinehydroxides, alkali carboxylates (e.g., sodium acetate), alkalicarbonates or hydrogen carbonates (e.g., sodium hydrogen carbonate),heterocyclic bases (e.g., substituted and unsubstituted pyrrolidine,pyrrolidinone, piperidine, piperidinone, pyrrole, pyridine, imidazole,benzimidazole, benzotriazole, and the like), amines and combinationsthereof. In some embodiments, the catalyst is or comprises an amine.Some non-limiting examples of suitable amines include alkylamines (e.g.,ethylamine), dialkylamines (e.g., diethylamine), trialkyamines (e.g.,triethylamine and N,N-diisopropylethylamine), arylamines (e.g.,phenylamine), diarylamines (e.g, diphenylamine), alkylarylamines (e.g.,N-methylaniline), triarylamines (e.g., triphenylamine),dialkylarylamines (e.g., N,N-dimethylaniline), and alkydiarylamines(e.g., N-methyldiphenylamine). In one embodiment, the catalyst is orcomprises triethylamine, unsubstituted imidazole or a combinationthereof.

In certain embodiments, the catalyst is or comprises a carboxylic acidhaving Formula (XI):R⁸—CO₂H  (XI)wherein R⁸ is alkyl, aryl, alkaryl, aralkyl, heterocyclyl or acombination thereof. In some embodiments, the carboxylic acid is orcomprises an aliphatic carboxylic acid such as acetic acid. In furtherembodiments, the catalyst comprises at least one of the amines and atleast one of the carboxylic acid of Formula (XI) disclosed herein. In aparticular embodiment, the catalyst comprises triethylamine and aceticacid.

The solvent for the condensation reaction may be any solvent that candisperse or dissolve both the 3-aminophthalic acid or a salt thereof andthe 3-aminoglutarimide compound of Formula (X) or a salt thereof.Non-limiting examples of suitable solvents include acetonitrile, ethylacetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran,dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide,dimethyl sulfoxide, toluene, isopropyl acetate, isopropyl alcohol,n-propanol and combinations thereof. In one embodiment, the solvent isacetonitrile.

The condensation reaction temperature can be any temperature useful forthe reaction of according to a person of ordinary skill in the art. Forinstance, in certain embodiments, the condensation reaction temperaturecan be from about 25° C. to about 100° C.

The condensation reaction time can be any time useful for the reactionaccording to a person of ordinary skill in the art. For instance, thereaction time can vary from about 1 to about 48 hours, depending on thereaction temperature. In general, the higher the reaction temperature,the shorter is the reaction time. In a particular embodiment, thereaction time is from about 5 hours to about 7 hours at a reactiontemperature from about 80° C. to about 90° C.

In one embodiment, the compound of Formula (I) is4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (i.e., whereR¹ of Formula (I) is H) which is prepared according to Scheme E below.Referring to Scheme E, 3-aminophthalic acid hydrochloride [i.e.,Compound (1)] reacts with 3-aminoglutarimide (i.e., where R¹ of Formula(X) is H) hydrochloride [i.e., Compound (2)] in a solvent such asacetonitrile in the presence of a catalyst comprising triethylamine andacetic acid. In some embodiments, the mole ratio of triethylamine toacetic acid is from about 1:10 to about 10:1. In other embodiments, themole ratio of triethylamine to acetic acid is from about 1:10 to about1:1. In further embodiments, the mole ratio of triethylamine to aceticacid is about 1:2.

The 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound ofFormula (I) can be purified by any conventional purification techniquessuch as recrystallization, extraction, chromatography and the like. Insome embodiments, the compound of Formula (I) is purified byrecrystallization. In other embodiments, the compound of Formula (I) is4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (i.e., where R¹of Formula (I) is H) which can be purified by recrystallization with asolvent mixture comprising dimethyl sulfoxide and water. In furtherembodiments, the ratio of dimethyl sulfoxide to water in the solventmixture is from about 1:10 to about 10:1 by volume. In a furtherembodiment, the ratio of dimethyl sulfoxide to water in the solventmixture is about 1:4 to about 1:8 by volume.

Particular embodiments of the present invention are illustrated by thesyntheses of Examples 1-17 according to Schemes A-E and modifocationsthereof. Modifications of variables including, but not limited to,reaction solvents, reaction times, reaction temperatures, reagents,starting materials, and functional groups in the particular embodimentsof the synthesis of4-amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione or an acid saltthereof will be apparent to those of ordinary skill in the art.

6. EXAMPLES Example 1 Preparation of N-(3-nitrophthaloyl)-glutamineAccording to Scheme C

A mixture of DMF (37 L), 3-nitrophthalic anhydride (4080 g, 21.1 moles)and L-glutamine (3020 g, 20.7 moles) was added to a round bottom flaskequipped with a mechanical stirrer, a condenser, a thermometer, anitrogen inlet and a heating mantel. The reaction mixture was stirred at80-87 ° C. for 8 hours. The temperature of the reaction was kept below90° C. at all time. The progress of the reaction was monitored by HPLCusing a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4 micron,UV wavelength=240 nm, retention time=3.64 minutes) and a 10/90 mixtureof acetonitrile and 0.1% aqueous H₃PO₄ by volume as an eluent at a flowrate of 1 mL/min. After the reaction was completed, the reaction mixturewas allowed to cool to room temperature and then concentrated to an oil(about 90% of DMF was removed) under a reduced pressure (400 mtorr atpump) on a heating bath at 40° C. The oil was stirred with water (39.7L) for 6 hours to produce a slurry. The solid in the slurry wasfiltered, washed with water (8.8 L), air dried and then dried in avacuum oven at 60° C. and <1 mm pressure. The yield of the crude productwas 4915 g (92.9% purity by HPLC). The crude product was furtherpurified by dispersing it in ethyl acetate in a ratio of 10 mL of ethylacetate to 1 g of the crude product. After the dispersion was stirredovernight, it was then filtered and the solid filtered out was dried toyield 4780 g (70%) of the product. The product purity was found to be99.62% by HPLC using a Waters Nova-Pak/C18 column (3.9×150 mm, particlesize=4 micron, UV wavelength=240 nm, retention time=5.0 minutes) and aneluent mixture of acetonitrile and 0.1% aqueous H₃PO₄ in a ratio of10:90 by volume at a flow rate of 1 mL/min. The product in DMSO-d₆ wascharacterized by a ¹H NMR spectrum showing the following chemical shifts(δ, ppm): 13.32 (b, 1 H), 8.33 (d, J=7.9 Hz, 1 H), 8.22 (d, J=7.4 Hz, 1H), 8.11 (t, J=7.8 Hz, 1 H), 7.20 (s, 1 H), 6.47 (s, 1 H), 4.83-4.77(dd, J=4.6 and 9.7 Hz, 1 H), 2.37-2.12 (m, 4 H); and by a ¹³C NMRspectrum showing the following chemical shifts (δ, ppm): 173.24, 170.05,165.44, 162.77, 144.47, 136.71, 133.00, 128.85, 127.27, 122.55, 51.88,31.32, 23.89. The melting point of the product was found to be 180-182°C. An elemental analysis yielded the following results in weightpercent: C, 48.75; H, 3.48; N, 13.07, which compared with calculatedvalues for C₁₃H₁₁N₃O₇, in weight percent: C, 48.60; H, 3.45; N, 13.08.

Example 2 Preparation of N-(3-Aminophthaloyl)-glutamine According toScheme B

A mixture of Example 1 (4780, 14.88 moles), 10% Pd/C (120 g) andmethanol (44 L) was hydrogenated at 50 psi for 2.5 hours in a 100 Lhydrogenation reactor. The progress of the reaction was monitored byHPLC using a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4micron, UV wavelength=240 nm, retention time=3.64 minutes) and an eluentmixture of acetonitrile and 0.1% aqueous H₃PO₄ in a ratio of 10:90 byvolume at a flow rate of 1 mL/min. The mixture was filtered through apad of celite and the celite pad was washed with methanol (6 L). Thefiltrate was concentrated in vacuo to a gummy material. The gummymaterial was stirred with ethyl acetate (22 L) overnight to form aslurry. The slurry was filtered and the yellow solid filtered out waswashed with ethyl acetate (10 L). The yellow solid was air dried andthen dried in a vacuum oven at 60° C. and <1 mm pressure to yield 423.0g of the product. The product purity was found to be 99.75% by HPLCusing a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4 micron,UV wavelength=240 nm, retention time=3.64 minutes) and an eluent mixtureof acetonitrile and 0.1% aqueous H₃PO₄ in a ratio of 10:90 by volume ata flow rate of 1 mL/min. The product in DMSO-d₆ was characterized by a¹H NMR spectrum showing the following chemical shifts (δ, ppm): 13.10(b, 1 H), 7.50-7.43 (dd, J=7.0 and 8.4 Hz, 1 H), 7.24 (s, 1 H),7.03-6.98 (dd, J=5.0 and 8.4 Hz, 2 H), 6.75 (s, 1 H), 6.52 (s, 2 H(,4.70-4.64 (dd, J=4.5 and 10.5 Hz, 1 H), 2.41-2.04 (m, 4 H); and by a ¹³CNMR spectrum showing the following chemical shifts (δ, ppm): 173.16,170.81, 168.94, 167.68, 146.70, 135.41, 132.07, 121.63, 110.93, 108.68,50.77, 31.38, 24.08. The melting point of the product was found to be177-179° C. An elemental analysis yielded the following results inweight percent: C, 53.61; H, 4.47; N, 14.31, which compared withcalculated values for C₁₃H₁₃N₃O₅, in weight percent: C, 53.60; H, 4.50;N, 14.43.

Example 3 Preparation of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione According toScheme A

A mixture of acetonitrile (42 L) and Example 2 (2120 g, 7.28 moles) wasadded to a round bottom flask equipped with a mechanical stirrer, acondenser, a nitrogen inlet and a heating mantel to form a solution.When the solution was stirred and heated to about 40 to 45° C.,1,1′-carbonyldiimidazole (1290 g, 7.95 moles) was added. The reactionmixture was stirred and refluxed for 4.5 hours. The progress of thereaction was monitored by HPLC using a Waters Nova-Pak C18 column(3.9×150 mm, particle size=4 micron, UV wavelength=240 nm, retentiontime=3.64 minutes) and an eluent mixture of acetonitrile and 0.1%aqueous H₃PO₄ in a ratio of 20:80 by volume at a flow rate of 1 mL/min.After cooled to room temperature, the reaction mixture was filtered toyield a yellow solid which was subsequently washed with acetonitrile(6.5 L). The yellow solid was air dried and then dried in a vacuum ovenat 60° C. and <1 mm pressure to yield 1760 g (88%) of the product. Theproduct purity was found to be 99.57% by HPLC using a Waters Nova-PakC18 column (3.9×150 mm, particle size=4 micron, UV wavelength=240 nm,retention time=3.64 minutes) and an eluent mixture of acetonitrile and0.1% aqueous H₃PO₄ in a ratio of 20:80 by volume as at a flow rate of 1mL/min. The product in DMSO-d₆ was characterized by a ¹H NMR spectrumshowing the following chemical shifts (δ, ppm): 11.10 (s, 1 H), 7.47 (t,J=7.9 Hz, 1 H), 7.03-6.99 (dd, J=4.8 and 8.4 Hz, 2 H), 6.52 (s, 2 H),5.09-5.02 (dd, J=5.3 and 12.4 Hz, 1 H), 2.96-2.82 (m, 1 H), 2.62-2.46(m, 2 H), 2.07-2.00 (m, 1 H); and by a ¹³C NMR spectrum showing thefollowing chemical shifts (δ, ppm): 172.82, 170.11, 168.57, 167-37,146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. Themelting point of the product was found to be 315.5-317.5° C. Anelemental analysis yielded the following results in weight percent: C,56.98; H, 3.86; N, 15.35, which compared with calculated values forC₁₃H₁₁N₃O₄, in weight percent: 57.14; H, 4.06; N, 15.38.

Example 4 Preparation of 3-Nitro-N-ethoxycarbonyl-phthalimide Accordingto Scheme D

Ethyl chloroformate (1.89 g, 19.7 mmol) was added dropwise over 10minutes to a stirred solution of 3-nitrophthalimide (3.0 g, 15.6 mmol)and triethylamine (1.78 g, 17.6 mmol) in DMF (20 mL) at about 0-5° C.under nitrogen. The reaction was allowed to warm to room temperature andstirred for 4 hours. The reaction mixture was slowly added to anagitated mixture of ice and water (60 mL). The slurry was filtered andthe solid was crystallized from CHCl₃ (15 mL) and petroleum ether (15mL) to yield 3.1 g (75%) of the product as an off-white solid: mp100.0-100.5° C.; ¹H NMR (CDCl₃) δ 8.25(d, J=7.5 Hz, 1 H), 8.20(d, J=8.0Hz, 1 H), 8.03(t, J=7.9 Hz, 1 H), 4.49(q, J=7.1 Hz, 2 H), 1.44(t, J=7.2Hz, 3 H); ¹³C NMR (CDCl₃) δ 161.45, 158.40, 147.52, 145.65, 136.60,132.93, 129.65, 128.01, 122.54, 64.64, 13.92; HPLC, Waters Nova-Pak/C18,3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄(aq), 5.17min (98.11%); Anal. calculated for C₁₁H₈N₂O₆: C, 50.00; H, 3.05; N,10.60. Found: C, 50.13; H, 2.96; N, 10.54.

Example 5 Preparation of t-Butyl N-(3-nitrophthaloyl)-L-glutamine

A mixture of Example 4 (1.0 g, 3.8 mmol), L-glutamine t-butyl esterhydrochloride (0.9 g, 3.8 mmol) and triethylamine (0.54 g, 5.3 mmol) inTHF (30 mL) was refluxed for 24 hours. The THF solvent was removed invacuo and the residue was dissolved in CH₂Cl₂ (50 mL). The CH₂Cl₂solution was washed with water (2×15mL) and brine (15 mL) and thendried. The solvent was removed and the residue was purified by flashchromatograph (CH₂Cl₂:EtOAc/7:3) to give 0.9 g (63%) of a glassymaterial: ¹H NMR (CDCl₃) δ 8.15(d, J=7.9 Hz, 2 H), 7.94(t, J=7.8 Hz, 1H), 5.57(b, 2 H), 4.84(dd, J=5.1 and 9.7 Hz, 1 H), 2.53-2.30(m, 4 H),1.43(s, 9 H); HPLC, Waters Nova-Pak/C18, 3.9×150 mm, 4 micron, 1 mL/min,240 nm, 30/70 CH₃CN/0.1% H₃PO₄(aq), 6.48 min (99.68%); Chiral Analysis,Daicel Chiral Pak AD, 0.4×25 Cm, 1 mL/min, 240 nm, 5.32 min. (99.39%);Anal. calculated for C₁₇H₁₉N₃O₇: C, 54.11; H, 5.08; N, 11.14. Found: C,54.21; H, 5.08; N, 10.85.

Example 6 Preparation of N-(3-Nitrophthaloyl)-L-glutamine

Hydrogen chloride gas was bubbled into a stirred cold (5° C.) solutionof Example 5 (5.7 g, 15.1 mmol) in CH₂Cl₂ (100 mL) for 25 minutes. Themixture was then stirred at room temperature for 16 hours. Ether (50 mL)was added and the resulting mixture was stirred for 30 minutes. Theslurry was filtered to yield 4.5 g of solid, which was used in the nextreaction: ¹H NMR (DMSO-d₆) δ 8.36(dd, J=0.8 and 8.0 Hz, 1 H), 8.24(dd,J=0.8 and 7.5 Hz, 1 H), 8.11(t, J=7.9 Hz, 1 H), 7.19(b, 1 H), 6.72(b, 1H), 4.80(dd, J=3.5 and 8.8 Hz, 1 H), 2.30-2.10(m, 4 H).

Example 7 Preparation of(S)-3-(3′-Nitrophthalimido)-piperidine-2,6-dione

A suspension mixture of Example 6 (4.3 g, 13.4 mmol) in anhydrous CH₂Cl₂(170 mL) was cooled to −40° C. with an isopropyl alcohol (IPA)/dry icebath. Thionyl chloride (1.03 mL, 14.5 mmol) was added dropwise followedby pyridine (1.17 mL, 14.5 mmol). After 30 minutes, triethylamine (2.06mL, 14.8 mmol) was added and the mixture was stirred at about −30 to−40° C. for 3 hours. The mixture was filtered and washed with CH₂Cl₂ toyield 2.3 g (57%) of the crude product. The crude product wasrecrystallized from acetone (300 mL) to yield 2 g of the product as awhite solid: mp 259.0-284.0° C. (dec.); ¹H NMR (DMSO-d₆) δ 11.19(s, 1H), 8.34(d, J=7.8 Hz, 1 H), 8.23(d, J=7.1 Hz, IH), 8.12(t, J=7.8 Hz, 1H), 5.25-5.17(dd, J=5.2 and 12.7 Hz, 1 H), 2.97-2.82(m, 1 H),2.64-2.44(m, 2 H), 2.08-2.05(m, 1 H); ¹³C NMR (DMSO-d₆) δ 172.67,169.46, 165.15, 162.50, 144.42, 136.78, 132.99, 128.84, 127.27, 122.53,49.41, 30.84, 21.71; HPLC, Waters Nova-Pak/C18, 3.9×150 mm, 4 micron, 1mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄(aq), 4.27 min.(99.63%); Anal.calculated for C₁₃H₉N₃O₆: C, 51.49; H, 2.99; N, 13.86. Found: C, 51.67;H, 2.93; N, 13.57.

Example 8 Preparation of(S)-3-(3′-Aminophthalimido)-piperidine-2,6-dione

A mixture of (S)-3-(3′-nitrophthalimido)-piperidine-2,6-dione (0.76 g,2.5 mmol) and 10% Pd/C (0.3 g) in acetone (200 mL) was hydrogenated in aParr-Shaker apparatus at 50 psi of hydrogen for 24 hours. The mixturewas filtered through celite and the filtrate was concentrated in vacuo.The solid was stirred with hot ethyl acetate for 30 minutes to give 0.47g (69%) of the product as a yellow solid: mp 309-310° C.; ¹H NMR(DMSO-d₆) δ 11.10 (s, 1 H), 7.47(dd, J=7.2 and 8.3 Hz, 1 H),7.04-6.99(dd, J=6.9 and 8.3 Hz, 2 H), 6.53(s, 2 H), 5.09-5.02(dd, J=5.3and 12.4 Hz, 1 H), 2.96-2.82(m, 1 H), 2.62-2.46(m, 2 H), 2.09-1.99(m, 1H); ¹³C NMR (DMSO-d₆) δ 172.80, 170.10, 168.57, 167.36, 146.71, 135.44,131.98, 121.69, 110.98, 108.54, 48.48, 30.97, 22.15; HPLC, WatersNova-Pak/C18, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 15/85 CH₃CN/0.1%H₃PO₄(aq), 4.99 min. (98.77%); Chiral analysis, Daicel Chiral Pak AD,0.46×25 cm, 1 mL/min, 240 nm, 30/70 Hexane/IPA 9.55 min.(1.32%), 12.55min(97.66%); Anal. calculated for C₁₃H₁₁N₃O₄: C, 57.14; H, 4.06; N,15.38. Found: C, 57.15; H, 4.15; N, 14.99.

Example 9 Preparation of t-Butyl N-(3-nitrophthaloyl)-D-glutamine

A mixture of Example 4 (5.9 g, 22.3 mmol), D-glutamine t-butyl ester(4.5 g, 22.3 mmol) and triethylamine (0.9 g, 8.9 mmol) in THF (100 mL)was refluxed for 24 hours. The mixture was diluted with CH₂Cl₂ (100 mL)and washed with water (2×50 mL), brine (50 mL) and dried. The solventwas removed in vacuo and the residue was purified by flashchromatography (2% CH₃OH in CH₂Cl₂) to afford 6.26 g (75%) of theproduct as a glassy material: ¹H NMR (CDCl₃) δ 8.12(d, J=7.5 Hz, 2 H),7.94(dd, J=7.9 and 9.1 Hz, 1 H), 5.50(b, 1 H), 5.41(b, 1 H), 4.85(dd,J=5.1 and 9.8 Hz, 1 H), 2.61-2.50(m, 2 H), 2.35-2.27(m,2 H), 1.44(s, 9H); ¹³C NMR (CDCl₃) δ 173.77, 167.06, 165.25, 162.51, 145.07, 135.56,133.78, 128.72, 127.27, 123.45, 83.23, 53.18, 32.27, 27.79, 24.42; HPLC,Waters Nova-Pak/C18, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 25/75CH₃CN/0.1% H₃PO₄(aq) 4.32 min.(99.74%); Chiral analysis, Daicel ChiralPak AD, 0.46×25 cm, 1 mL/min, 240 nm, 55/45 Hexane/IPA 5.88min.(99.68%); Anal. calculated for C₁₇H₁₉N₃O₇: C, 54.11; H, 5.08; N,11.14. Found: C, 54.25; H, 5.12; N, 10.85.

Example 10 Preparation of N-(3-Nitrophthaloyl)-D-glutamine

Hydrogen chloride gas was bubbled into a stirred cold (5° C.) solutionof Example 9 (5.9 g, 15.6 mmol) in CH₂Cl₂ (100 mL) for 1 hour thenstirred at room temperature for another hour. Ether (100 mL) was addedand stirred for another 30 min. The mixture was filtered, washed withether (60 mL) and dried (40° C., <1 mm Hg) to afford 4.7 g (94%) of theproduct: ¹H NMR (DMSO-d₆) δ 8.33(d, J=7.8 Hz, 1 H), 8.22(d, J=7.2 Hz, 1H), 8.11(t, J=7.8 Hz, 1 H), 7.19(b, 1 H), 6.72(b, 1 H), 4.81(dd, J=4.6and 9.7 Hz, 1 H), 2.39-2.12(m, 4 H); ¹³C NMR (DMSO-d₆) δ 173.21, 169.99,165.41, 162.73, 144.45, 136.68, 132.98, 128.80, 127.23, 122.52, 51.87,31.31, 23.87.

Example 11 Preparation of(R)-3-(3′-Nitrophthalimido)-piperidine-2,6-dione

A suspension mixture of Example 10 (4.3 g, 13.4 mmol) in anhydrousCH₂Cl₂ (170 mL) was cooled to −40° C. with EPA/dry ice bath. Thionylchloride (1.7 g, 14.5 mmol) was added dropwise followed by pyridine (1.2g, 14.5 mmol). After 30 minutes, triethylamine (1.5 g, 14.8 mmol) wasadded and the mixture was stirred at −30 to −40° C. for 3 hours. Themixture was filtered, washed with CH₂Cl₂ (50 mL) and dried (60° C., <1mm Hg) to give 2.93 g of the product. Another 0.6 g of the product wasobtained from the methylene chloride filtrate. Both fractions werecombined (3.53 g) and recrystallized from acetone (450 mL) to afford2.89 g (71%) of the product as a white solid: mp 256.5-257.5° C.; ¹H NMR(DMSO-d₆) δ 11.18(s, 1 H), 8.34(dd, J=0.8 and 7.9 Hz, 1 H), 8.23(dd,J=0.8 and 7.5 Hz, 1 H), 8.12(t, J=7.8 Hz, 1 H), 5.22(dd, J=5.3 and 12.8Hz, 1 H), 2.97-2.82(m, 1 H), 2.64-2.47(m, 2 H), 2.13-2.04(m, 1 H); ¹³CNMR (DMSO-d₆) δ 172.66, 169.44, 165.14, 162.48, 144.41, 136.76, 132.98,128.83, 127.25, 122.52, 49.41, 30.83, 21.70; HPLC, Waters Nova-Pak/C18,3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1 % H₃PO₄(aq) 3.35min.(100%); Anal. calculated for C₁₃H₉N₃O₆: C, 51.49; H, 2.99; N,13.86.Found: C, 51.55; H, 2.82; N, 13.48.

Example 12 Preparation of(R)-3-(3′-Aminophthalimido)-piperidine-2,6-dione

A mixture of Example 11 (1.0 g, 3.3 mmol) and 10% Pd/C (0.2 g) inacetone (250 mL) was hydrogenated in a Parr-Shaker apparatus at 50 psiof hydrogen for 4 hours. The mixture was filtered through celite and thefitrate was concentrated in vacuo. The yellow solid was slurried in hotEtOAc (20 mL) for 30 minutes to give 0.53 g (59%) of the product as ayellow solid: mp 307.5-309.5° C.; ¹H NMR (DMSO-d₆) δ 11.06(s, 1 H),7.47(dd, J=7.0 and 8.4 Hz, 1 H), 7.02(dd, J=4.6 and 8.4 Hz, 2 H),6.53(s, 2 H), 5.07(dd, J=5.4 and 12.5 Hz, 1 H),2.952.84(m, 1 H),2.62-2.46(m, 2 H), 2.09-1.99(m, 1 H); ¹³C NMR (DMSO-d₆) δ 172.78,170.08, 168.56, 167.35, 146.70, 135.43, 131.98, 121.68, 110.95, 108.53,48.47, 30.96, 22.14; HPLC, Waters Nove-Pak/C18, 3.9×150 mm, 4 micron, 1mL/min, 240 mn, 10/90 CH₃CN/0.1% H₃PO₄(aq), 3.67 min.(99.68%); Chiralanalysis, Daicel Chiral Pak AD, 0.46×25 cm, 1 mL/min, 240 nm, 30/70Hexane/IPA 7.88 min. (97.48%); Anal. calculated for C₁₃H₁₁N₃O₄: C,57.14; H, 4.06; N, 15.38. Found: C, 57.34; H, 3.91; N, 15.14.

Example 13 Preparation of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione According toScheme E

A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, fromProsynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g,0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), andacetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into areaction vessel. After the mixture was stirred for 15 minutes,triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) wasadded dropwise over 30-35 minutes while the reaction temperature wasmaintained at 20-25° C. Next, the reaction mixture was stirred furtherfor 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to7 hours or until the in-process control, i.e., HPLC AP at 240 nm,indicates that <2% of the 3-aminophthalic acid remained in the reactionmixture. After the reaction mixture was cooled to about 20 to 25° C.over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. forabout 20 to 30 minutes to provide a yellow solid precipitate, which wasfiltered, washed with DI water (3×1.0 L) and acetonitrile (2×500 mL),and then dried at about 35 to 40° C in vacuo to a constant weight at210.0 g (84 %).

Example 14 Preparation of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione

Example 14 was prepared similarly according to the procedure for Example13 except that there was no acetic acid; the amount of triethylamine wasreduced from 4.6 mol to 3.2 mol; and the refluxing time was increasedfrom about 5 to 7 hours to about 47 hours. The amount of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reactionmixture was found to be 94%.

Example 15 Preparation of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione

Example 15 was prepared similarly according to the procedure for Example13 except that there was no acetic acid and the 4.6 mol of triethylaminewas replaced with 9.2 mole of imidazole. The amount of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reactionmixture was found to be 92%.

Example 16 Preparation of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione

Example 16 was prepared similarly according to the procedure for Example13 except that the 4.6 mol of triethylamine was replaced with 9.2 moleof imidazole. The amount of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reactionmixture was found to be 85%.

Example 17 Recrystallization of4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione

The 4-amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione racemates andstereomers such as Examples 3, 8, and 12-16 can be purified byrecrystallization as described below. A mixture of crude Example 13 (200g) and DMSO (800 mL) was charged into a reaction vessel. The resultingslurry was heated to about 45 to 50° C. and then stirred until fulldissolution of the solid was achieved (about 10 to 15 minutes). Theresulting solution was clarified at about 45 to 50° C. followed by aDMSO (400 mL) line rinse at about 45 to 50° C. The solution was added topurified water (7.2 L) at about 75 to 80° C. over at least 60 minutes.The resulting suspension was cooled to about 15 to 20° C. over at least1.5 hours and stirred at the same temperature for about 1.5 to 2 hours.The suspension was filtered and the solid was washed with purified water(2×2 L). The purified product was dried under vacuum at about 35 to 40°C. until constant weight is attained. The yield of the purified productwas 196.8 g (98% recovery). The melting point of the purified productwas found to be 321-323° C.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples that are intended as illustrationsof a few aspects of the invention and any embodiments that arefinctionally equivalent are within the scope of this invention. Indeed,various modifications of the invention in addition to those shown anddescribed herein will become apparent to those skilled in the art andare intended to fall within the appended claims. All references cited ordisclosed herein are incorporated herein by reference in their entirety.

1. A process for preparing a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, polymorph orstereoisomer thereof, comprising the step of cyclizing a compound ofFormula (II) or (IIA):

or a salt thereof with a cyclizing agent of Formula (V):

wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; and each of X and Y is independently an unsubstituted orsubstituted imidazolyl, benzimidazolyl or benzotriazolyl.
 2. The processof claim 1, wherein the compound of Formula (II) is cyclized.
 3. Theprocess of claim 1, wherein the compound of Formula (IIA) is cyclized.4. The process of claim 1, wherein the compound of Formula (I) is asolvate which is a hydrate.
 5. The process of claim 1, wherein thecompound of Formula (I) is a racemic mixture, the (+)-enantiomer or the(−)-enantiomer.
 6. The process of claim 1, wherein the cyclizing agentis a carbonyldiimidazole compound.
 7. The process of claim 6, whereinthe carbonyldiimidazole compound is 1,1′-carbonyldiimidazole.
 8. Theprocess of claim 7, wherein the ratio of the compound of Formula (II) or(IIA) to 1,1′-carbonyldiimidazole is from about 1:1 to about 1:1.2. 9.The process of claim 7, wherein the cyclizing step occurs in a solvent.10. The process of claim 9, wherein the solvent is acetonitrile orN-methyl pyrrolidinone.
 11. The process of claim 10, wherein the solventis acetonitrile and the reaction temperature is from about 80° C. toabout 87° C.
 12. The process of claim 11, wherein the reaction time isfrom about 1 hour to about 5 hours.
 13. The process of claim 1, whereinR¹ is H
 14. The process of claim 1, wherein the compound of Formula (II)or (IIA) is prepared by reducing a compound of Formula (III) or (IIIA)respectively:

with a reducing agent, wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈) alkynyl.
 15. The process of claim 14, whereinthe reducing agent is hydrogen and 10% Pd/C.
 16. The process of claim15, wherein the hydrogen is at a pressure from about 2.76 bars to about3.45 bars.
 17. The process of claim 15, wherein the reaction occurs in asolvent.
 18. The process of claim 17, wherein the solvent is methanol.19. The process of claim 14, wherein R¹ is H.
 20. The process of claim14 wherein the compound of Formula (III) or (IIIA) is prepared byreacting 3-nitrophthalic anhydride with a compound of Formula (IV) or(IVA) respectively:

wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl.
 21. The process of claim 20, wherein the reaction occursin a solvent.
 22. The process of claim 21, wherein the solvent isdimethyl formamide.
 23. The process of claim 21, wherein the reactiontemperature is from about 80° C. to about 87° C.
 24. The process ofclaim 23, wherein R¹ is H.
 25. The process of claim 1, wherein thecompound of Formula (I) is a free amine.
 26. The process of claim 25,further comprising a step of reacting the free amine with an acid in amole ratio of about 1:1 to form an acid salt.
 27. The process of claim26, wherein the acid is hydrochloric acid.
 28. The process of claim 14,wherein the compound of Formula (III) is prepared by the steps of: (a)reacting 3-nitro-N-ethoxycarbonyl-phthalimide with a glutamine esterhaving Formula (VIII):

or an acid salt thereof in the presence of a first catalyst to form acompound of Formula (IX) or a salt, solvate, polymorph or stereoisomerthereof:

(b) reacting the compound of Formula (IX) or a salt, solvate, polymorphor stereoisomer thereof with hydrogen chloride, wherein R¹ is H, F,benzyl, (C₁-C₈)alkyl, (C₂-C₈) alkenyl, or (C₂-C₈)alkynyl; and R⁸ isalkyl or aralkyl.
 29. The process of claim 28 further comprising a stepof preparing the 3-nitro-N-ethoxycarbonyl-phthalimide by reacting3-nitrophthalimide with ethyl chloroformate in the presence of a secondcatalyst.
 30. The process of claim 29, wherein the first catalyst andthe second catalyst are each triethylamine.
 31. The process of claim 28,wherein R¹ is H; and R⁸ is t-butyl or benzyl.
 32. The process of claim31, wherein the compound of Formula (VIII) is L-glutamine t-butyl esterhydrochloride and the compound of Formula (III) is the (S)-enantiomer.33. The process of claim 31, wherein the compound of Formula (VIII) isD-glutamine t-butyl ester hydrochloride and the compound of Formula(III) is the (R)-enantiomer.
 34. The process of claim 31, wherein thecompound of Formula (VIII) is a racemic mixture of glutamine t-butylester hydrochloride and the compound of Formula (III) is a racemicmixture.
 35. A process for preparing a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, polymorph orstereoisomer thereof, comprising the step of reacting 3-aminophthalicacid or a salt thereof with a 3-aminoglutarimide compound of Formula (X)or a salt thereof:

in a solvent, wherein R¹ is H, F, benzyl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,or (C₂-C₈)alkynyl.
 36. The process of claim 35, wherein R¹ is H.
 37. Theprocess of claim 35, wherein the compound of Formula (I) is a racemicmixture, the (+)-enantiomer or the (−)-enantiomer.
 38. The process ofclaim 35, wherein the reacting step occurs in the presence of a catalystwhich is a base, an acid or a combination thereof.
 39. The process ofclaim 38, wherein the catalyst is the base.
 40. The process of claim 39,wherein the base is a trialkylamine, a substituted or unsubstitutedimidazole or a mixture thereof.
 41. The process of claim 38, wherein thecatalyst is a combination of the base and the acid.
 42. The process ofclaim 41, wherein the base is an amine and the acid is a carboxylicacid.
 43. The process of claim 42, wherein the amine is triethylamineand the carboxylic acid is acetic acid.
 44. The process of claim 43,wherein the mole ratio of triethylamine to acetic acid is from about1:10 to about 1:1.
 45. The process of claim 35, wherein the solvent isacetonitrile.
 46. The process of claim 45, wherein the reactiontemperature is from about 80° C. to about 87° C.
 47. The process ofclaim 46, wherein the reaction time is from about 5 hours to about 7hours.